Gilead Sciences, Inc., 1651 Page Mill Road, Palo Alto, CA 94304, USA.
Am J Physiol Regul Integr Comp Physiol. 2011 Aug;301(2):R491-9. doi: 10.1152/ajpregu.00756.2010. Epub 2011 May 18.
Contractile reserve decreases with advancing age and chronic isoproterenol (ISO) administration is a well-characterized model of cardiac hypertrophy known to impair cardiovascular function. This study evaluated whether nonsenescent, mature adult rats are more susceptible to detrimental effects of chronic ISO administration than younger adult rats. Rats received daily injections of ISO (0.1 mg/kg sc) or vehicle for 3 wk. ISO induced a greater impairment in contractile reserve [maximum of left ventricular pressure development (Δ+dP/dt(max))] in mature adult ISO-treated (MA-ISO) than in young adult ISO-treated rats (YA-ISO) in response to infusions of mechanistically distinct inotropes (digoxin, milrinone; 20-200 μl·kg(-1)·min(-1)), while basal and agonist-induced changes in heart rate and systolic arterial pressure (SAP) were not different across groups. ISO decreased expression of the calcium handling protein, sarco(endo)plasmic reticulum Ca(2+)-ATPase-2a, in MA-ISO compared with YA, YA-ISO, and MA rats. Chronic ISO also induced greater increases in cardiac hypertrophy [left ventricular (LV) index: 33 ± 3 vs. 22 ± 5%] and caspase-3 activity (34 vs. 5%) in MA-ISO relative to YA-ISO rats. Moreover, β-myosin heavy chain (β-MHC) and atrial natriuretic factor (ANF) mRNA expression was significantly elevated in MA-ISO. These results demonstrate that adult rats develop greater impairments in systolic performance than younger rats when exposed to chronic catecholamine excess. Reduced contractile reserve may result from calcium dysregulation, increased caspase-3 activity, or increased β-MHC and ANF expression. Although several studies report age-related declines in systolic performance in older and senescent animals, the present study demonstrates that catecholamine excess induces reductions in systolic performance significantly earlier in life.
收缩储备随着年龄的增长而减少，慢性异丙肾上腺素（ISO）给药是一种众所周知的心脏肥大模型，已知会损害心血管功能。本研究评估了未衰老的成年大鼠是否比年轻的成年大鼠更容易受到慢性 ISO 给药的不利影响。大鼠每天接受 ISO（0.1mg/kg sc）或载体注射 3 周。ISO 诱导成熟成年 ISO 处理大鼠（MA-ISO）的收缩储备（左心室压力发展的最大程度（Δ+dP/dt(max)））比年轻成年 ISO 处理大鼠（YA-ISO）更严重受损，以响应机械上不同的正性肌力药（地高辛，米力农；20-200 μl·kg(-1)·min(-1)）的输注，而心率和收缩压（SAP）的基础和激动剂诱导变化在各组之间没有差异。ISO 降低了钙处理蛋白肌浆内质网 Ca(2+)-ATPase-2a 在 MA-ISO 中的表达，与 YA、YA-ISO 和 MA 大鼠相比。慢性 ISO 还诱导了更大的心脏肥大增加[左心室（LV）指数：33±3%对 22±5%]和 MA-ISO 中 caspase-3 活性（34%对 5%）比 YA-ISO 大鼠增加。此外，β-肌球蛋白重链（β-MHC）和心钠素因子（ANF）mRNA 表达在 MA-ISO 中显著升高。这些结果表明，暴露于慢性儿茶酚胺过多时，成年大鼠比年轻大鼠表现出更大的收缩功能障碍。收缩储备的降低可能是由于钙调节异常、caspase-3 活性增加或β-MHC 和 ANF 表达增加所致。尽管有几项研究报道了老年和衰老动物中收缩功能的年龄相关下降，但本研究表明，儿茶酚胺过多会导致收缩功能在生命早期明显下降。
